Cell Death in Huntington's Disease: Emory Researchers Study the Causes
disease (HD) is a hereditary disorder of the central nervous system
that develops in adulthood and can cause of a wide range of symptoms.
A faulty gene which produces a protein called huntingtin causes HD.
That faulty gene leads to damage of the brain cells or neurons, then
gradual physical, mental and emotional changes follow.
Researchers at Emory University,
along with researchers at Duke University and University of British
Columbia, Canada, are trying to determine how and why these neurons
die and what role the mutant huntingtin protein plays in killing these
brain cells. The findings will appear in the electronic publication
of Nature Neuroscience on July 1, 2002, and in a later print publication
of the journal.
"I think there is little
doubt that the mutant huntingtin protein does several different harmful
things to neurons," says J. Timothy Greenamyre, M.D., Ph.D., medical
director of the Huntington's Disease Society of America (HDSA) Center
of Excellence at Emory University and professor of neurology, Emory
University School of Medicine. "The huntingtin protein dramatically
alters which cellular genes turn on and off, activates cell death pathways
and alters mitochondrial function. At first glance, this might seem
to make our attempts to unravel HD terribly difficult, but it also presents
more 'targets' at which we can aim new treatments," Dr. Greenamyre explains.
Dr. Greenamyre's lab is studying
the mitochondrial function in HD. Mitochondria produce energy for the
cells. Past studies have shown that mitochondria in HD do not function
properly. "By impairing the function of mitochondria in lab rodents,
we have noticed the brain cells that die in the rodents are the same
cells that die in Huntington's disease," says Dr. Greenamyre. "This
finding helps us to reproduce many of the features of HD."
Besides producing energy
for the cell, normal mitochondria also help to regulate calcium levels
within neurons, preventing the levels from rising too high, which can
cause cell damage or death. Mitochondria in HD have problems with this
regulation process and, in turn, release calcium and other harmful chemicals
into the cell interior. The results are cell damage and death. Dr. Greenamyre
describes normal mitochondria as having a charge like a battery. When
the battery runs down, he explains the process is similar to mitochondria
in HD. The mitochondria in HD do not have a full charge, he says. The
Emory researchers have also discovered that HD mitochondria depolarize
or short-circuit differently from normal mitochondria.
"Our research has also helped
us determine how the mutant huntingtin protein alters mitochondrial
function," Dr. Greenamyre points out. "By exposing normal mitochondria
to the mutant huntingtin protein, we've found they begin to behave like
HD mitochondria. They can no longer take up a normal amount of calcium
and they begin to short-circuit when the calcium levels are too low."
More studies still need to
be conducted to better define these mitochondrial abnormalities. However,
Dr. Greenamyre's research suggests that medications designed to improve
mitochondrial function should be beneficial in patients with Huntington's
disease. Whether those patients should be given the drugs when the abnormal
gene is recognized or wait until the disease further progresses, is
Right now, doctors can only
treat the symptoms of Huntington's disease, which include involuntary
movements, loss of intellectual faculties, difficulty in speech and
swallowing, mood swings and depression. Currently there is no cure for
the illness. About 30,000 Americans have HD and about 150,000 more are
at risk of inheriting the disease from a parent.